Abstract 2258: Starvation response to chemotherapy induces MHC class 1 upregulation in cancer cells
Authors: Reshma Gurung, Alehegne Yirsaw, Mohammad Hassan, Temesgen Samuel, Clayton Yates, Deepa Bedi
Journal: Cancer Research (2023)

Abstract In tumor Major Histocompatibility Complex (MHC) class 1 expression pathway, antigen presenting peptides get hijacked and thus cancer cells escape immune recognition and promote immunosuppressive microenvironment. The restoration of altered MHC 1 expression is important for the treatment of cancer. Inhibition of amino acid uptake or tRNA synthase which mediates amino acid incorporation into protein, mimics starvation. The cancer cell responds to starvation by upregulating proteases to mobilize fatty acids and cellular surface molecules to scavenge exogenous molecules. EPRS (Glutamyl prolyl tRNA synthetase) catalyzes the aminoacylation of glutamic acid and proline to cognate tRNAs. Apart from that, the overexpression of EPRS1 gene is related to tumor angiogenesis, but the mechanism is not clear. Research showed that inhibition of EPRS is effective for the inhibition of triple negative breast cancer (TNBC) and colon cancer. Camptothecin (CPT) is a kind of chemotherapy drug that causes DNA damage by binding topoisomerase enzyme and DNA complex and arrest cells cycle in the S and G2 phases resulting in apoptosis. The knockdown (KD) of EPRS in TNBCs and the use of CPT for the treatment of colon cancer are both likely to have an impact on the accumulation of self epitopes, PTMs, and the creation of neoepitopes within tumors as a result. In this study, we examined the effects of EPRS and CPT treatment on the stimulation of MHC 1 in TNBC and colon cancer cells, as well as the diversity of peptide repertoires in EPRS KD breast cancer cells and CPT treated colon cancer cells. We conducted flow cytometer to detect the HLA specific antibodies on CPT treated RKO and SW620 colon cancer as well as EPRS KD MDA MB 231 triple negative breast cancer cells in our laboratory. In addition, we also performed immunopeptidomes on these cell lines to gain a deeper understanding of the biochemistry and immune pathway. Furthermore, we conducted cell cycle assays in both CRISPR and lentiviral mediated EPRS KD MDA MB 231 cells after CPT treatment. The human MHC class 1 expression were higher in both CPT treated RKO and SW620 colon cancer and EPRS KD MDA MB 231 TNBC cells as compared to the control in both our laboratory and Cayman Immunopeptidome analysis tests. In addition, the cell cycle result showed increment in S phase and reduction in G1 phase in some of the CPT treated EPRS KD ShRNA samples as compared to the control. These results showed that CPT as well as EPRS may play some role in the MHC Class 1 presentation in cancer cells. There were no significant changes observed in the total peptide content of TNBC cells after EPRS knockdown and colon cancer cells after CPT treatment. However, the knockdown of EPRS gene and the CPT treatment resulted in a novel peptide repertoire presented by the cells, which could have relevant to antigen presentation. Further studies are needed for detailed understanding of the biochemistry and immune pathway. Citation Format: Reshma Gurung, Alehegne Yirsaw, Mohammad Hassan, Temesgen Samuel, Clayton Yates, Deepa Bedi. Starvation response to chemotherapy induces MHC class 1 upregulation in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2258.